Narrator - Dr. Abel 00:00 Welcome to HelixTalk, an educational podcast for healthcare students and providers, covering real life clinical pearls, professional pharmacy topics and drug therapy discussions. Narrator - ? 00:11 This podcast is provided by pharmacists and faculty members at Rosalind Franklin University, College of Pharmacy. Narrator - Dr. Abel 00:17 This podcast contains general information for educational purposes only. This is not professional advice, and should not be used in lieu of obtaining advice from a qualified health care provider. Narrator - ? 00:27 And now on to the show. Dr. Sean Kane 00:31 Welcome to HelixTalk episode 180 I'm your co host, Dr. Kane, and I'm Dr. Patel, and the title of today's episode is the ultimate guide to statins and in depth drug class review. So, Dr. Patel, today we're talking about statins and everything a clinician needs to know about this really important drug class. Dr. Khyati Patel 00:47 This is really exciting because I teach it and so it's going to be an additional tool that I can give my students to review on the side. So thank Dr. Sean Kane 00:54 you for doing this perfect Well, why don't we start with just brain and generic names? And you know, when I teach really any pharmacotherapy topic, Dr. Patel, I always go through and I pronounce the brand and generic names because I think it's really important that as healthcare providers, we call the drug the way it's supposed to be called, right, right. Dr. Khyati Patel 01:10 Generically, all the generic entities end in statin, and then we have different brand names thereafter. Yep. Dr. Sean Kane 01:18 So we have atorvastatin (brand name Lipitor), fluvastatin (brand name Lescol), lovastatin (brand name Mevacor) and pitavastatin (brand name Livalo). Dr. Khyati Patel 01:28 And then additionally we have pravastatin (brand name Pravachol), rosuvastatin (brand name Crestor) and simvastatin (brand name Zocor). And as we know, the statin, especially the simvastatin, is available in combination with ezetimibe (brand name Vytorin) if you happen to see it. Dr. Sean Kane 01:48 So Dr. Todd. I think most people know, even patients. They know that this is their cholesterol medication, but they may not know exactly how it works. I think most pharmacy students know that these are HMG COA reductase inhibitors, which is sometimes the drug class, as opposed to calling them statins, although that's a mouthful. So most people know that there's an enzyme that is inhibited, but maybe don't know to connect the details of how that results in a beneficial effect for Dr. Khyati Patel 02:13 a patient, right? And I like to, you know, just like I tell my patients, I tell to the students too, there's two ways your body can be getting LDL, it's what your liver makes, which is like an intrinsic pathway, and the other one is what you eat, right your like your diet and things like that. So intrinsic, pathway wise, it blocks these enzyme called HMG COA reductase in the liver. That particular enzyme is responsible for converting HMG COA into malenic acid that then goes to production of cholesterol. By blocking it, using the statins, we are basically stopping this cholesterol production, and that's why statins are called HMG COA reductase inhibitor, Dr. Sean Kane 02:54 and we know that that's the primary mechanism, which is LDL reduction, or bad cholesterol reduction, by blocking your liver's ability to make LDL cholesterol. But we also know that there's some magic, or pleiotropic effect that comes along with statins. What is a pleiotropic effect? Dr. Khyati Patel 03:10 A pleiotropic effect is basically something that is provided in addition to this main effect, the main effect is LDL reduction, but additionally, we see with statins that it does help reduce risk of cardiovascular disease such as heart attack and stroke. And so there is this beautiful effect of statins for reducing inflammation, reducing or stabilizing that plaque, the atherosclerotic plaque, that goes even beyond what LDL reduction benefits that these statins Dr. Sean Kane 03:41 provide, and we don't exactly know. I mean, we have hypotheses of how that happens, but that's where the word pleiotropic comes in. Of Yeah, it does something else. We're just not exactly sure, but it's a good thing, whatever that thing is, yeah, Dr. Khyati Patel 03:53 we have many different statins, as we covered earlier, to kind of provide an overview, like, how exactly do they impact the LDL as primarily, as we explained, via mechanism, that's the target, and then if there are any effects on other lipoproteins, yeah. Dr. Sean Kane 04:09 So it depends on the potency of the statin and the dose, but on the low end, you're going to reduce LDL by about 20% and on the high end, about 60% remember, LDL is your bad cholesterol, so you know, by reducing it more than half. That's actually our therapeutic goal in certain high risk patients. Dr. Khyati Patel 04:24 Yeah, and the other lipoproteins that we focus on is our high density lipoprotein, which is actually a good lipoprotein, as well as triglycerides, which is, that's a good one. The statins tend to have some effect, not not as great of an effect as it they do on LDL, but they can help improve HDL by about 10% and they could help lower the triglycerides anywhere between 10 to 30% but again, if you're looking at your high intensity statins, they tend to provide the highest triglyceride reduction. Dr. Sean Kane 04:55 And again, the main reason we're using these statins is for LDL reduction, so it's assuring or. Good thing that these other lipid numbers are improving versus getting worse. Our main focus so is that LDL cholesterol for these statins, right? Dr. Khyati Patel 05:08 And then, aside from statins, we do have other non statin medications that could help us lower the LDL, just kind of comparing where statins kind of stand among these non statin therapies. Dr. Sean Kane 05:21 So ezetimibe (Zetia) is roughly a 15–20% LDL reduction, which is on the very low end compared to a statin. Bempedoic acid (Nexletol) is also about 15–20%. The really impressive reductions come from PCSK9 inhibitors like evolocumab (Repatha) or alirocumab (Praluent); these lower LDL by around 50–60%, typically on top of what you get from a statin. That class requires injections and is expensive. Dr. Khyati Patel 06:05 And technically they are approved for those with high ascvd risk, where LDL is not a goal, but we're going to see this in niche patient population, such as those with either heterozygous or homozygous familial hypocholesterolemia, no Dr Dr. Sean Kane 06:21 tell whenever we do these episodes on HelixTalk, where we kind of do a drug class review, one of the most interesting things for me is like, what is the difference between statin a and statin B, or N said a and n said b, or SSRI a versus SSRI B? So why don't we take some time to talk about what are the differences between the statins, as opposed to the similarities? Dr. Khyati Patel 06:40 Yeah, and I mean, comes to specific knowledge required by pharmacists, this is kind of what we are known for. So let's dive into the differences. Dr. Sean Kane 06:49 So the first difference is LDL lowering in terms of how good of a job we do. And we kind of alluded to this earlier. But not all statins are created equal when it comes to how much they lower your LDL by, yeah. Dr. Khyati Patel 06:58 So we kind of roughly have three categories per se, high intensity, which are categorized as those that lower LDL by 50% or more. We have the moderate intensity statins that lower the LDL somewhere between 30 to 50% and then we have the low intensity that will lower the LDL by 30% or less. Dr. Sean Kane 07:19 And I think you know, we're not going to go through each one, but just to give a couple examples the high dose, high potency category, this is going to be a torva statin, 40 to 80 milligrams, or rosuvastatin, 20 to 40 milligrams once a day. Yeah. Dr. Khyati Patel 07:33 And then if you look at the moderate intensity statin, again, we have many examples, but agents like simvastatin, 20 to 40 milligram, or pravastatin 40 to 80 milligram fall into this range. Dr. Sean Kane 07:45 And then that low intensity statin category is kind of interesting, because we almost never start patients in this category, but patients may end up here if they don't tolerate higher doses. So a couple examples would be simvastatin 10 milligrams, pravastatin 10 or 20 milligrams. So these are really low intensity, low dose statins that we don't typically use unless a patient is intolerant to a higher dose regimen, right? Dr. Khyati Patel 08:07 And if you really need to move the needle, meaning make an impactful change in the LDL, rather than changing the intensity, for example, going from 10 milligram of pravastatin to 40 milligram of pravastatin, it's actually just better to change the agent altogether so that you are looking at additional LDL reduction. Dr. Sean Kane 08:27 And numerically, doubling the dose gives you roughly a six ish percentage point difference in your LDL. So even if you quadrupled your dose, you're looking at 12 percentage points lower for your LDL versus if you go to that high dose statin, it could be a much bigger magnitude of benefit, right? Dr. Khyati Patel 08:44 And then they also differ in terms of their half life. And then that's why we tell patients to take them at a specific time. So the longer half life statins tend to be those high potency LDL reducing statins. And then most of these Statins have longer half life, rearranging it between, you know, 12 hours to 19 hours, even some active metabolites of a tortoise statin leading up to 30 hours of half life. Dr. Sean Kane 09:14 But most of the other statins that aren't as long acting, they're going to have half lives that are measured in just single digit number of hours, so like one to three hours. And because of that, the recommendation is when you're taking these shorter, Half Life statins. So that's not atorvastatin, rosuvastatin or pitavastatin, but all of the other ones, the recommendation is to take these at night, because most of your cholesterol production occurs at night, and you're trying to maximize the peak effect of the drug with the peak cholesterol production, right? Dr. Khyati Patel 09:44 So you could get away by telling your patients, if they're getting an atorvastatin, rosuvastatin or pitavastatin, that they can technically take it at any time of the day, rather than taking it at night. But all the other ones, they'll have to take it at night. There comes a little bit of patient specific or. Shared decision making point too. If your patient tells you, hey, you know, I fall asleep and miss my night, medications like five times out of the seven nights, perhaps it's the good idea to change them to a long acting statins if they qualify for that high intensity, and then that way they can take it any time of the day. Dr. Sean Kane 10:17 And just to put a number to it, there's been at least two crossover trials where they've compared taking it at night versus taking it during the day, mostly with simvastatin, and the difference is about five to 10 percentage points of LDL reduction. So it's enough that you would notice it, but it's not so much that it means that the statin has no effect at all if you take it in the morning, but agreed, like for the most part, if compliance at night is really that big of a problem, it's probably just better to use a long acting statin. There statin. They're very inexpensive now, where two, three decades ago, they worked, so cost is really not as big of a factor anymore, right? Dr. Khyati Patel 10:49 Because they are all now available as generic, so that's good. The other way they differ is their metabolism. What pathway they take to be processed matters. We all know about the CYP3A4 metabolism – that's our agents such as atorvastatin. It’s also going to go through simvastatin and lovastatin. There are other statins, such as fluvastatin, pitavastatin, and rosuvastatin; they go through CYP metabolism, but they are not heavily reliant on the 3A4 isoform. The one I like to point out that’s a little bit different is pravastatin. It doesn’t go through the CYP system at all; it goes through glucuronidation. So if you have patients on CYP3A4 substrates, inducers, or inhibitors, a medication like pravastatin can come in handy, because then we’re not looking for those drug interactions. Dr. Patel, Dr. Sean Kane 11:41 I think that's important enough that we just highlight one more time. So pravastatin generally has the fewest drug interactions. Simvastatin, atorvastatin and lovastatin tend to have more or the most drug interactions, and then all the other statins are kind of in the middle. They do go through CYP enzyme systems, but they're not heavily reliant on 3A4, so you can see interactions, but maybe not as much as those top three, which again, were lovastatin, simvastatin and atorvastatin. So you know, we take these to lower cholesterol, right? Dr. Patel, but we also take them, really, for the bigger benefit of not having heart attacks and not having strokes, right? So it's great if your LDL is better, but we've seen drugs historically that make your lipid panel better, but don't change your risk of heart disease. So do we? Hopefully we see a benefit in terms of heart disease with these right we do. Dr. Khyati Patel 12:28 You would say again, this depends on the intensity of the statin as well. But if you're looking at our higher intensity statin, we are looking at about 35 to 45% reduction our lower intensity or lower potency statins, we're looking at 15 to 25% so on average, about 30% reduction we see in these events such as heart attack and stroke. So then, Dr. Sean Kane 12:53 if you think about it, you know, for the audience that's familiar with the ascvd 10 year risk calculation, that's your risk of having, effectively, a heart attack or a stroke in the next 10 years. If your percent is 10% that means that if you take a statin, instead of being at 10% risk, you'll go down to 7% a 30% reduction, so you still have a risk. It's lower, and that 30% is roughly the clinical benefit that we observe. Dr. Khyati Patel 13:17 Yeah, and if we are talking about patients who are using statins for something called primary prevention, meaning they they haven't had an event yet, they haven't had a heart attack or a stroke, versus those people who are now taking it to prevent a secondary heart attack or secondary stroke. Is there a difference? Generally? Dr. Sean Kane 13:36 Yeah. So when we think about the number needed to treat, which is related to how big of a benefit you have, but also the incidence rate of that people who have had heart attacks and strokes are more likely to have heart attacks or strokes in the future compared to someone who's never had it. So generally speaking, the number needed to treat, or the number of patients that are going to benefit from statin therapy is going to be better or higher if you are focused on a secondary prevention population versus a primary prevention population. But both populations definitely do benefit from statin therapy. Dr. Khyati Patel 14:06 And earlier, we compared the statins with the non statin agents for their LDL reduction. How do statins compare with some of these non statins when it comes to reducing this ascvd events? Dr. Sean Kane 14:17 So it's actually not even competitive. Dr. Patel, so statins are way, way better when it comes to reducing your risk of heart attack and stroke. Now with that said, all of the other non statin therapies, generally, have been studied with background therapy of statin so that means that their benefit is on top of statin therapy. So you have to take that into account. But remember, statins have roughly a 30% relative risk reduction. Ezetimibe (Zetia) is only about 6%, and that benefit was really only seen in the IMPROVE‑IT trial, which was a very specific high‑risk population. Bempedoic acid (Nexletol) is about 13%, which is better but still not 30%. Our PCSK9 inhibitors – evolocumab (Repatha) and alirocumab (Praluent) – have impressive LDL reduction, yet their relative risk reduction is only about 15%, so they’re still a bit better than bempedoic acid and ezetimibe, but not at the 30% level. So statins really are the king in terms of having the most bang for your buck for ASCVD risk reduction. Dr. Khyati Patel 15:19 And this is great coverage of statins effect, right in terms of LDL reduction versus their impact on this cardiovascular morbidity and mortality. But now, if we can boil it down and talk about what patients are made for statins, who should get statins, and to what intensity statins they should get it. So we do have this link to our show note, but there is a 2018 ACCA blood cholesterol guidelines. According to the guidelines, there are four different categories of patients that are considered our statin groups, or statin benefiting patients. Dr. Sean Kane 15:56 So for primary prevention, remember, these are patients who have never had a heart attack, stroke, peripheral arterial disease, the symptomatic those patients might get a statin if their LDL is really high, so 190 or higher, which generally is in the category of this familial hypercholesterolemia, it's a genetic predisposition versus a bad diet, for example. So they definitely qualify. Dr. Khyati Patel 16:20 These patients are going to get actually, a high intensity statin. Then we have patients with diabetes who are between 40 to 75 years of age, and we're looking at their LDL level between 70 to 189 and the recommendation is to at least start with moderate intensity. And then if they have one or more ascvd risk factors, hypertension, obesity, you know, all that stuff, then they could go up to high intensity statin and Dr. Sean Kane 16:48 then our third primary prevention group are patients that don't have diabetes, don't have a really high LDL, but they do have an elevated ASCD risk, that 10 year risk, and most of the data is Those that have a risk of 7.5% or higher. So in the next 10 years, the risk is seven and a half percent or higher. But the guidelines do say that you might consider it kind of a gray area for the five to seven and a half percent patients. It's more shared decision making, looking at other risk factors, things like that. Yeah. Dr. Khyati Patel 17:16 And then the category or the potency of statin that's recommended for this subgroup is moderate intensity statin. And so we covered three benefit groups so far, Dr. Kane, the last one is obviously patients who had an event before, right? So these are our secondary prevention patients. They had a stroke or a heart attack, or maybe they got a, you know, four vessel cabbage done, or something like that. These patients are going to be indicated for statins, and the recommendation is to go with high intensity statin. So Dr. Kane, this was a good review of, you know, who are these four categories of statin benefiting patients and what intensity statins we should put them on. One thing I wanted to provide a disclaimer of is for most other pharmacotherapy, talking about blood pressure therapy, blood sugar therapy, you're going to see an initial dose or kind of have this mantra call start low, go slow. When it comes to these statins and these benefiting groups, you want to go with the intensity of statin that is recommended. So if it says high intensity, we go with the high intensity. If they don't tolerate the high intensity, maybe we can, you know, move it down to moderate or add other non statin therapy as needed. But we don't do the Start low, go slow approach with statins. Dr. Sean Kane 18:33 So we kind of alluded to this already, Dr. Patel, but there are drug interaction considerations when it comes to statins. And the first category is the one that we already talked about, which is cytochrome P450 3A4 inhibition. So remember, it's atorvastatin, simvastatin, lovastatin that heavily rely on 3A4. So if you have a drug that inhibits the 3A4 pathway, those statin drug levels in the blood are going to go up, and you're more likely to see a side effect from too much statin drug concentration. Dr. Khyati Patel 19:01 yes, fluconazole all comes to mind as one example. If you look up the label for simvastatin, you would see plenty of drug interaction, because they did a study on it, and now you have limitation of like, okay, if you're using amlodipine with it, you can't go more than 20 milligram of simvastatin. It's, again, agent specific, but yes, these drug interactions are real, especially with atorvastatin and lovastatin. Dr. Sean Kane 19:27 other one is jimfi Brazil. And this is actually pretty relevant, because it's not that uncommon that patients have mixed dyslipidemia where they have high triglycerides and they might want to fibrate and a high LDL and they might want a statin. So what's going on with Dr. Khyati Patel 19:41 this one? The bottom line I tell students to do is do not use gemfibrozil. It's a type of fibrate or fenofibric‑acid category medication. It works by lowering triglycerides. And so with patients who are having – we call it mixed dyslipidemia, where their triglycerides are high and their LDL is high – we need a therapy that can help lower the triglycerides. Gemfibrozil is going to actually interfere with statin glucuronidation during that phase‑II metabolism. So again, the bottom line is, you know, try not to use it. If you look at some statin package inserts, use of gemfibrozil is actually a contraindication, and some statins don't have it. Also, gemfibrozil requires dosing two or three times a day, so why add that pill burden? We do have other fibrate‑class medications such as fenofibrate that do have interactions with statins, but they are much safer than gemfibrozil when combined with a statin. Dr. Sean Kane 20:47 We should say that again, the risk here is that statin drug levels can get too high. You get muscle pain, which we'll talk about soon. It's toxicity of the statin that we're worried about in the same vein grapefruit juice. And I think anyone who's ever worked in a pharmacy probably remembers all the do not drink grapefruit juice stickers that come along with that prescription bottle. And interestingly, but probably not surprisingly, that the impact of grapefruit juice as an interaction depends on which statin you're looking at. Dr. Khyati Patel 21:13 Yeah, that's really interesting. And I have students telling me sometimes, oh, I read somewhere like, you shouldn't do more than 1.2 liter. And I'm like, Who drinks 1.2 liter, let alone someone like me who cannot tolerate grapefruit juice or grapefruit but let's say one example, right? Look at simu San. It says, you know, 200 milliliters once daily could cause almost four time increase in AUC area under the curve, or C max, which is the maximum concentration of the drug, Dr. Sean Kane 21:43 and that would be basically like a glass of grapefruit juice. So it's not like 1.2 liters. We'll get to the 1.2 liters in a second, but that's like a normal amount of grapefruit juice that if you consume it four fold increase. That's like you took four simvastatin tablets instead of one. That's actually a really big deal, right? Dr. Khyati Patel 21:59 And this could easily lead to those myopathy style side effects. Dr. Sean Kane 22:04 So then atorvastatin does have this interaction, but isn't as notable in terms of the magnitude of effect. So there was a study that looked at a similar volume, 240 milliliters of grapefruit juice, and it basically increased atorvastatin drug levels a little bit, but not that much. But then they there was another study looked at 200 milliliters of double strength, which I didn't even know was the thing, but double strength grapefruit juice three times a day, so a dramatically higher dose, and that tripled your atorvastatin drug level. So this is where that 1.2 liters comes in. Is 200 mls times two because it's double strength times three, because it's three times a day. That's where the 1.2 liters comes in, which is actually in the package insert for atorvastatin. And as you said, like, I can't even stomach the thought of drinking more than a liter of grapefruit juice. I don't know where that comes from. Dr. Khyati Patel 22:53 Yeah, that's a that's a big amount, per se. And then if you look at private statin, there is no drug interaction at all. Right, so again, this grapefruit interaction is definitely specific to certain statins. Dr. Sean Kane 23:05 Yeah, and so really, you know, if someone wants to have a glass of grapefruit juice while on atorvastatin, that’s probably not a big deal, but if they consume quite a bit of it, it could be a big deal with simvastatin or lovastatin; you don't need much grapefruit juice to get a profound increase in drug level. Dr. Khyati Patel 23:23 Well, aside from these drug interactions, we do definitely educate patients on statin side effect, and there are pretty prevalent side effects out there, especially the myalgia, but we do have some rare side effects to discuss as well, and there is a lot of focus on side effect and how to manage statins based on these side effects in the guideline itself as well. So definitely check out the show Note link. Dr. Sean Kane 23:52 What's interesting? So we'll start with the most common one, which is myalgias, and this is where the patient's having muscle pain, but if you check their blood levels of creatine phosphokinase or Cpk or ck, it's normal, so you don't have biochemical evidence of muscle damage, but they're having muscle pain that can be pretty limiting in terms of being able to walk without pain and things like that. Dr. Khyati Patel 24:15 Yeah. And if you if you were to ask patient to describe what that muscle pain is like, they're going to say, oh, it's happening in both of my thighs, right? So we're talking about bilateral presentation in very proximal muscles, so bigger muscle systems. And it could occur anywhere from weeks to months after statin therapy starting, and if it's really coming from statin and the way to find out this is if you stop the statin and give them 10 to 14 days without statins, and if they say, yes, my muscle pain might obey, then we can confirm that it really came from the statin. Dr. Sean Kane 24:49 And this is really the only clearly common adverse effect of our statins. When I say clearly common, I mean the incidence rate is up to 20% and real. Patients may be as low as 5% which is probably more accurate. And interestingly, in randomized, controlled trials, it's a little bit lower one to 5% probably in a self selecting group of patients that are a little bit healthier. So this is definitely a side effect that occurs, and we have a pretty good sense of the incidence rate is not less than 1% let's say Dr. Khyati Patel 25:18 yeah, but the ones that are fairly rare with spam therapy are then myopathy. And I have to do, I do have to teach students the difference between what is myalgia versus what is myopathy. So myopathy is when you have that myalgia, muscle pain. But then you would also see a lab abnormality. So you'll see an elevated Cpk levels. This is, again, really rare you would see with statins warning of rhabdomyolysis. Again, this is a severe type of muscle breakdown that manifests not only with muscle pain, but also very elevated Cpk. We are talking 10 times the upper limit of normal and when the muscle breakdown happens, our body produces myoglobin, which is technically toxic to the kidneys, so patients may also present with acute renal failure. Dr. Sean Kane 26:08 Then there's some side effects that have kind of come out more in observational studies. And I would say we're not exactly sure if statins definitely cause it, or if it's more Association versus causation, but one that has come up more recently is an increased risk of the development of diabetes, and the risk kind of depends on what the patient's intrinsic risk of diabetes is, so overweight already has an elevated fasting glucose value, something like that, but the risk is roughly 9% increased risk over about four years. So an odds ratio of 1.09 which isn't nothing, but also not that dramatic either, right? Dr. Khyati Patel 26:47 And if you look at the studies that showed this, probably is studies that use high intensity statins, or higher doses of statins. And when it comes to, you know, patients with diabetes complaining that, oh, this may disrupt my blood sugar. I tell them, It's better to not have a stroke or a heart attack when you have diabetes, but your risk is really high than have a little bit of elevation in blood sugar that we can manage with your anti hyperglycemic Absolutely. Dr. Sean Kane 27:15 So in my mind, this is a non issue, because the benefit of the statin clearly outweighs the risk of developing diabetes. Absolutely. Dr. Khyati Patel 27:23 The other one is increase in LFTs. I almost think that the manufacturers should take that away from the labeling, because we don't get to see it. It's very rare and infringement. In fact, patients who have the fatty liver disease, they would inherently because there is scarring on the liver tissues and stuff, and injury to the hepatocyte, they would have increased lfds. But hey, the treatment for this patient is actually statin therapy. Because fatty liver disease, it's the fat deposit. We need to bring it down, right? So you could use statins in patients who have liver injury, as long as it's not acute liver injury. However, the pure association of how statins cause liver injury is really, really rare. Dr. Sean Kane 28:12 Then our last one, which is probably the least proven connection to statins, is memory or cognitive impairment. This is really rare. We've seen some case reports kind of focusing on this, but there's at least been three RCTs, randomized, controlled trials that have said that this is not a thing. So patients may ask about this. And in my opinion, the data is not clear enough. This is definitely a side effect associated Dr. Khyati Patel 28:33 with statins, yeah. And if you look at some Alzheimer's studies that came out recently, it says it's actually helps to reduce amyloid plaques, right? So there is a beneficial effect seen in some of the trials. Nonetheless, if you have an older patient where you're collaboratively, be talking with the providers and patients and their caregivers and be like, really, the statins doing it, you could stop the statins. Obviously, risk versus benefit should be discussed, and the memory impairment actually is reversible. Dr. Sean Kane 29:03 So in terms of the statin associated muscle symptoms, and this is actually abbreviated in the guidelines as s AMS, statin associated muscle symptoms, this is the main side effect, right? So are there risk factors? And what do we do if a patient does experience s AMS, Dr. Khyati Patel 29:17 yeah, so they have listed a pretty good number of risk factors. One is older patients. And how are they defined? 75 and older is how they are defined. Female patients tend to be at a higher risk, those who have lower body weight, those patients who exercise. I'm talking weight lifting, not just like mild or moderate aerobics, so heavy exercising patients, and then obviously patients who have potential for drug interactions, right? So we talked about some of the drugs earlier, but even those who are using non statin therapies for their mixed dyslipidemia, these patients are going to be at a higher risk. And so this is a huge intervention point for the pharmacist to have in order to mitigate some of. Is drug interaction, right? Grapefruit was one example. That's an easy, easy fix, easier fix than actual drug interaction. But yeah, these are, these are our risk factors for statin associated muscle symptoms. Dr. Sean Kane 30:12 So then, if you think your patient is having that in collaboration with the prescriber, the steps would be to stop the statin and see if it gets better. Yeah. And if it doesn't get better, it's not the statin. We know that it will improve with this continuation. But then if it does improve, what are our steps there? Are they never going to get a statin ever again? Probably not. But what do we do? Dr. Khyati Patel 30:33 Yeah, my motto is a little bit or something is better than nothing, so we should definitely try to reduce the dose of the same statin. So let's say the myalgia happened from simvastatin 40 milligram. We should try and see if they will tolerate simvastatin 20 milligram instead, or even 10 milligrams. So that's we're jumping the statin intensity category here. Or you could choose a different statin altogether, right? So for example, it's if the myalgia is really coming from the drug drug interaction, and we want to avoid that CYP interaction. Perhaps pravastatin would be a better choice for this patient. So changing that could also help. Dr. Sean Kane 31:10 I think what's promising is numerically, a majority of patients will be able to tolerate a statin, typically at a lower dose and alternative statin, as opposed to never been on a statin in the future. So it's worth it to try, because the majority of patients will be able to get on some statin therapy, as opposed to never being able to qualify for statin in the future, right? Dr. Khyati Patel 31:30 And I do see this in a patient's chart on and off, that they would be labeled as you know, they're intolerant to some of the statin. But then the provider, when trying to talk to the patient about risk reduction, they will just say, Oh, well, you're intolerant to statins. Don't labor your patient if they've just failed one statin, try other statins and see if they would work. Dr. Sean Kane 31:50 Dr. Patel, I know historically, some providers would give something like CO Q 10 or ubiquinone, because there was a thought that deficiencies of those two vitamins or supplements might be related to the myalgias that happen with statins. Is that a thing? Yeah. Dr. Khyati Patel 32:07 So you know, Chemically speaking and methodologically speaking, mechanism wise, that makes sense. Why would you want to replenish co Q 10? Because you're exhausting this ubiquinone molecule in the metabolism of the statins, but when you look at clinical trials, they did not improve the myalgia. So technically, there is no role in statin therapy. However, if a patient believes it's a sugar pill effect, right? If a patient believes that they are able to take their simvastatin or atorvastatin, because they are taking their CO Q 10. Let them do it because I’d rather them take the simvastatin or an atorvastatin than not take it at all. Dr. Sean Kane 32:50 So then in terms of when we start our statin therapy, so we already talked about that, probably statin labeling should be updated, about the lft risk and things like that. What types of labs do we need to get at baseline, and then what kinds of labs do we get on a recurrent basis? Dr. Khyati Patel 33:05 Yeah, I think with saying that about LFTs, I would still be more comfortable if I don't know the patient seeing them for the first time, that I evaluate LFTs at baseline before starting. Obviously you would want to know where their lipids are so you can compare when they come back for monitoring as to what their levels, how their how their levels are improving or not, right? So I would check their baseline lipid panel, and I would check their baseline liver panel, which would give you your LFTs. Dr. Sean Kane 33:35 So then, in terms of when you get that repeat lipid panel, you want to give enough time that their cholesterol numbers are impacted and kind of at a new steady state. So how long does that take? Dr. Khyati Patel 33:46 So the earliest you could do it is a month, so four weeks. You could do it up to 12 weeks. So four to 12 weeks, I'll tell you. In reality, in my clinic, we do it three months, if we if we do it, to check the efficacy of the statin. Dr. Sean Kane 34:02 And what's interesting is, you know, this isn't just your opinion of LFTs at baseline, repeat lipid panel and lipid panel at baseline. The guidelines literally weigh in on what do you get at baseline and what do you get on a routine basis, and they are very clear in terms of other stuff that you get after you've initiated therapy. You do not routinely need to get creatine phosphokinase or creatine kinase or CPK, Ck, and you do not need to get your lft, your liver function test routinely done. And this is really a departure from probably 20 years ago, when these were very commonly routinely done. The guidelines say do not do this, yeah, Dr. Khyati Patel 34:38 because we know statins don't cause the lft elevation, not not routinely again, and the injury to the muscle where you would see an elevation in CK or CPK is also very rare, so we don't need to waste lab money. However, if your patient does present with that muscle pain or weakness or have jaundice like symptoms. Where you think there is some liver issue going on, then you may want to use your clinical judgment and take it so again, not routinely, but only in certain patients. Dr. Sean Kane 35:08 So Dr. Phil, why don't we round out today's drug class review episode with some clinical pearls or counseling points that are notable that don't fit cleanly into a given category? So for me, one of those is statins are teratogenic, so you can't take a statin if you want to get pregnant, or you're pregnant, you have to stop the statin. Dr. Khyati Patel 35:29 The other category then we think about after pregnancy is, what about breastfeeding? Right? Well, when the baby is getting nutrition from mom, cholesterol is an important component of breastfeeding, so you don't want to limit the amount of cholesterol that that's being passed. However, there is, clinically speaking, there is not much data. How much drug enters the breast milk itself. Dr. Sean Kane 35:52 Of the data we have, it seems like it's not that much. So most of the don't breastfeed. Recommendation is more about nutrition to the baby versus drug exposure to the baby, right? And then the other category that comes up quite a bit is, you know, the guidelines are pretty specific about 40 to 75 years old, and that's the age category for qualifying for a statin, unless you have crazy high LDL. But what about those really old patients? So people who are more than 75 years of age, do they get a statin or not. And I see this all the time, that older individuals are on statins. But why do the guidelines draw that line at 75 Dr. Khyati Patel 36:27 years old? This is where the shared decision making comes in, right? Statin is, quote, unquote, adding statin is reasonable for both primary and secondary prevention for patients who are 75 years of age or about this is going to be that discussion between patient and the provider, whether you continue or not, and this is coming from some of the gaps we've seen in the randomized control trials in patients who are 75 years or older. So again, your benefit from statins doesn't come next year or two years later. It's usually very cumulative. So when you're looking at benefit of statin it's about 30% over 10 years, at 75 years of age. Are you really trying to increase a person's age by 10 more years, right? So again, looking at the lifespan, looking at the prognosis with multiple different comorbidities that these patients may have, it's really a patient, provider decision whether they continue or not. Dr. Sean Kane 37:22 And just to put some context to that, if you had an 80 year old who is still running marathons, and, you know, very active, very few comorbidities, but they have a statin indication, they're probably going to live till they're 90, and it makes sense to give them a statin. But if you have an 80 year old who's bed bound has had multiple strokes that has terrible quality of life. Maybe it doesn't make sense to give them a statin both, because they probably won't live long enough to derive the benefit, but they are potentially going to have some of the side effects and drug interactions associated with that statin therapy. Dr. Khyati Patel 37:57 Yeah, so you kind of balance out the benefit and the risk for sure, and then last but not the least, just like we say about other chronic disease medications, statins are chronic therapy. So yes, you may see a lab reduction in LDL within your four or 12 week of monitoring, but that other benefits of statins, where we are seeing reduction in mortality and morbidity of cardiovascular disease that doesn't come in a year, it doesn't come in months, it comes over years. And so when you are on statins, you're going to be on statins for a Dr. Sean Kane 38:33 long period of time. And you know this comes up frequently for API students in the ICU as an example, where they feel like, Oh, you have to give them their statin back, otherwise, they're going to have a heart attack. That's not true. So you can acutely stop a statin for a drug interaction or an acute illness or whatever the reason is, obviously we want our patients to take it as much as possible over a long period of time. But if they miss a week because they don't feel well, or they miss a week because they're they need to take paxlovid or whatever. That's not going to hurt the patient, because this is a long term chronic therapy, that the benefit is derived over years, not days or months, right? Dr. Khyati Patel 39:08 Because these plaques develop over years. So the benefits also come over years. Dr. Sean Kane 39:13 So kind of rounding out today's episode with a couple key points. One is that statins primarily reduce your LDL cholesterol, and it's somewhere between 20 and 60% depending on the statin selected and the dose picked, and they have a modest but favorable effect on HDL, cholesterol and triglycerides. Clinically, we use these because they help your LDL, but mainly we use them because they reduce your risk of heart attacks and strokes by about 30% and again, there's a range in terms of the benefit based on the potency of the statin, Dr. Khyati Patel 39:43 and there are four main groups of patients who are indicated for statins. These patients are those with LDL of 190 or above, those with diabetes and age of 40 to 75 years of age, but the LDL is between 70. To 180 those patients who do not have diabetes or ascvd but an elevated 10 year ascvd risk score of 7.5% or above, or even, you know, with decision making between five and 7.5% and then those patients who've had an ascvd event. So this is our secondary prevention patients. Dr. Sean Kane 40:21 And then, from a drug interaction standpoint, atorvastatin, lovastatin and simvastatin heavily rely on CYP3A4, and for that reason, they tend to be more prone to drug interactions versus something like pravastatin that goes through Phase Two metabolism. Dr. Khyati Patel 40:36 And again, this point, we can't emphasize enough, as pharmacists, we are involved in medication monitoring as well. So when you're starting a patient on statin baseline, you would want to get their lipid panel as well as lfds, but after four to 12 week, we can check the efficacy of statins. We can repeat a lipid panel. We do not have to repeat the liver function test or Cpk routinely. You could do it in patients who have accompanying symptoms such as muscle pain or jaundice like symptoms. Dr. Sean Kane 41:08 So that wraps up today's episode quite nicely. So a statin drug review. We do have a reference in our show notes, and that's at HelixTalk.com Again, this is episode 180 we're also on Apple podcasts and things like that, so we love the five star review and however you're listening to us today, and we also have a mailing list, so if you go to our website, HelixTalk.com you can subscribe, and you'll get an email whenever new episodes come out. So with that, Dr. Khyati Patel 41:33 I'm Dr. Kane and I'm Dr. Patel, and as always, study hard. Narrator - Dr. Abel 41:38 If you enjoyed the show, please help us climb the iTunes rankings for medical podcasts by giving us a five star review in the iTunes Store, search for HelixTalk and place your review there Narrator - ? 41:49 to suggest an episode or contact us. We're online at HelixTalk.com thank you for listening to this episode of HelixTalk. This is an educational production copyright Rosalind Franklin University of Medicine and Science.